Substituted 2-aminbenzothiazoles and derivatives useful as cerebrovascular agents

ABSTRACT

A series of substituted 2-aminobenzothiazoles and derivatives useful for treating cerebrovascular disorders are disclosed. Also disclosed is a new method for treating such disorders.

CROSS-REFERENCE TO RELATED APPLICATION

This is a divisional of U.S. application Ser. No. 143,107 filed Jan. 25,1988, now U.S. Pat. No. 4,826,860, which is a continuation-in-part ofU.S. application Ser. No. 026,428 filed Mar. 16, 1987, now abandoned.

BACKGROUND OF THE INVENTION

The compounds of the instant invention are a series of2-aminobenzothiazoles which are useful for treating cerebrovasculardisorders.

The present invention relates to a method of using certain2-aminobenzothiazoles and pharmaceutically acceptable salts thereof asagents in treating cerebrovascular disorders.

U.S. Pat. No. 4,370,338 covers 2-amino-6-trifluoromethoxybenzothiazoleas useful as an anticonvulsant, an anxiolytic, and a hypnotic. Thecompound is described in Chemical Abstracts 60, 692a, 1964. Othercompounds of the invention are novel.

Domino et al, in J. Pharm. Exp. Ther., 1952, 105, 486-497 and in 1953,107, 356-367 have described the pharmacological action of substitutedbenzazoles as inducing paralysis.

Paris et al, in Chimie Therapeutique, 1973, 6 655-658 discloses certain2-aminobenzothiazole derivatives as analgesics and antiinflammatories.

SUMMARY

The present invention relates to a new method for treatingcerebrovascular disorders. Such disorders are described hereinbelow. Themethod of treatment comprises administering a therapeutically effectiveamount of a compound of Formula I as described hereinafter.

Stroke is one cerebrovascular disorder in particular which can betreated by the instant method. Disorders including, but not limited to,cerebral ischemia or cerebral infarction resulting from a range ofconditions such as thromboembolic or hemorrhagic stroke can be treatedby the instant method.

Compounds of Formula I can also be used as anesthetics especially insurgical operations where risk of cerebrovascular damage exists.

Pharmaceutical compositions are also included.

DETAILED DESCRIPTION

The instant invention concerns a new method for treating cerebrovasculardisorders, such disorders are those in which excitatory amino acids, forexample, glutamatic and aspartic acids, are implicated. Such disordersinclude cerebral ischemia or cerebral infarction resulting from a rangeof conditions such as thromboembolic or hemorrhagic stroke, cerebralvasospasm, hypoglycemia, cardiac arrest, status epilepticus, or cerebraltrauma. Other treatments are for schizophrenia, epilepsy, neuromusculardisorders, Alzheimer's Disease, or Huntington's Disease. Still othermethods of use are as analgesics and anesthetics, especially asanesthetics in surgical operations where a finite risk ofcerebrovascular damage exists, for example, carotid endarterectomy.

This method of treatment comprises administering a therapeuticallyeffective amount of a compound of Formula I or a pharmaceuticallyacceptable salt thereof in unit dosage form. Formula I is ##STR1##wherein R¹ and R² may be the same or different and are hydrogen,

straight or branched alkyl of from one to six carbon atoms,

lower alkylaryl,

lower alkenyl,

phenyl,

CF₃,

hydroxy,

lower alkoxy,

lower alkylthio,

lower alkylsulphonyl,

CF₃ O, at the six position

halogen,

nitro,

carboxy,

lower alkoxycarbonyl,

NR⁵ R⁶ CO,

NR⁵ R⁶,

R⁵ CONR⁵,

CN,

NR⁵ R⁶ SO₂,

wherein R⁵ and R⁶ may be the same or different and are hydrogen, loweralkyl, or aryl;

R¹ and R² may together form a carbocyclic or methylenedioxy ring;

R³ is hydrogen;

R⁴ is hydrogen,

lower alkyl,

lower alkyl substituted by a heterocyclic group, or substitutedheterocyclic group,

methylcycloalkyl,

benzyl,

phenethyl,

phenyl,

phenyl substituted by,

halogen,

alkyl of one to six atoms,

alkoxy,

amino,

substituted amino,

carboxy,

cyano and,

nitro,

allyl

propargyl

with the proviso that R¹, R², and R³ must be hydrogen when R⁴ is otherthan hydrogen.

The term alkyl, except where otherwise stated, in alkyl per se, alkoxy,alkylaryl, alkylthio, alkylsulphonyl, alkoxycarbonyl is preferably alower alkyl of from one to six carbon atoms and may be straight orbranched.

Alkenyl means an unsaturated straight or branched chain of from one tosix carbon atoms.

Aryl in alkylaryl may contain from six to ten atoms and include groupssuch as phenyl and naphthyl.

Alkoxy means groups such as methoxy, ethoxy, propyloxy, and the like,and alkoxycarbonyl means an ester group, for example, methyl ester,ethyl ester, benzyl ester.

The term halogen means fluorine, chlorine, bromine, and iodine.

The term carbocyclic means groups such as, for example, benzene, orcyclohexyl.

The term heterocyclic ring includes 5 and 6-membered saturated compoundssuch as pyrrolidine, piperidine, and heteroaromatic groups such aspyridine and thiophene.

The term substituted heterocyclic group includes substitution by loweralkyl and alkenyl such as N-methylpyrrolidine and N-allylpyrrolidine.

For R⁴, phenyl may be substituted by halogen, alkyl of from one to sixcarbon atoms, alkoxy, amino, substituted amino, carboxy, cyano, andnitro.

The preferred compounds are those of Formula I wherein

R¹ and R² are hydrogen,

straight or branched alkyl of from one to six carbon atoms,

lower alkylaryl,

alkenyl

phenyl,

CF₃,

lower alkoxy,

lower alkylthio,

lower alkylsulphonyl,

CF₃ O at the six position,

halogen,

nitro,

NR⁵ R⁶,

R⁵ CONR⁵, or

CN;

R³ is hydrogen; and

R⁴ is hydrogen,

alkyl,

methylcycloalkyl, or

benzyl,

2-(1-methyl-2-pyrrolidinyl)ethyl,

with the proviso that R¹, R², and R³ must be hydrogen when R⁴ is otherthan hydrogen.

The more preferred compounds are:

2-aminobenzothiazole,

2-amino-6-methylbenzothiazole,

2-amino-4-methylbenzothiazole,

2-amino-6-trifluoromethylbenzothiazole,

2-amino-4-trifluoromethylbenzothiazole,

2-amino-5-trifluoromethylbenzothiazole,

2-amino-6-trifluoromethoxybenzothiazole,

2-amino-6-ethoxybenzothiazole,

2-amino-6-nitrobenzothiazole,

2-amino-4-methoxybenzothiazole,

2-amino-5-methoxybenzothiazole,

2-amino-4,6-dimethylbenzothiazole,

2-amino-6-bromobenzothiazole,

2-amino-6-chlorobenzothiazole,

2-amino-4-chlorobenzothiazole,

2-amino-6-fluoromethylbenzothiazole,

2-amino-naptho[1,2-d]thiazole,

2-ethylaminobenzothiazole,

2-[[2-(1-methyl-2-pyrrolidinyl)ethyl]amino]-benzothiazole,

2-amino-6-methylsulphonylbenzothiazole,

2-amino-4,6-difluorobenzothiazole,

2-amino-6-methylthiobenzothiazole, and

2-benzylaminobenzothiazole.

Compounds of the instant invention include solvates, hydrates, and saltsof the compounds of Formula I above.

A compound of Formula I above is useful both in the free base form andin the form of acid addition salts and both forms are within the scopeof the invention. The term pharmaceutically acceptable acid additionsalt is intended to mean relatively nontoxic acid addition salts fromeither inorganic or organic acids such as, for example, hydrochloric,hydrobromic, sulfuric, phosphoric, citric, oxalic, malonic, acetic,maleic, salicyclic, ethanesulfonic, malic, gluconic, fumaric, succinic,ascorbic, methanesulfonic, benzenesulfonic, p-toluenesulfonic and thelike as would occur to one skilled in the art.

Pharmaceutically acceptable inorganic and organic basic salts such assodium, calcium, lithium, potassium, magnesium, ammonium or quaternaryammonium salts, diethylamine, and diethanolamine are also within thescope of the invention.

The acid addition salts of the basic compounds are prepared either bydissolving the free base in aqueous or aqueous-alcohol solution or othersuitable solvents containing the appropriate acid and isolating the saltby evaporating the solution, or by reacting the free base and acid in anorganic solvent, in which case the salt separates directly or can beobtained by concentration of the solution. The basic addition salts aresimilarly prepared.

The compounds used in the invention may contain asymmetric carbon atoms.This invention includes the use of individual enantiomers ordiastereomers which may be prepared or isolated by methods known in theart.

The effectiveness of the aforementioned compounds is determined by apharmacological test procedure as described and illustrated as follows.

The procedure is entitled Combined Middle Cerebral and IpsilateralCommon Carotid Occlusion in the Rat as a Screen for Compounds Active inthe Treatment of Stroke (MCAO).

Occlusion of the proximal part of the middle cerebral artery (MCA) is acommon cause of stroke in man and can be accomplished surgically inexperimental animals. This technique, though technically feasible in therat is very difficult and time-consuming (Tamura, A., Graham, D. I.,McCulloch, J., Teasdale, G. M., Focal Cerebral Ischemia in the Rat: 1.Description of Technique and Early Neuropathological ConsequencesFollowing Middle Cerebral Artery Occlusion. J. Cereb. Blood Flow Metab.1:53-60, 1981). It has been reported that a distal occlusion of the MCA5 mm from its origin at the circle of Willis does not consistentlyresult in infarction (Coyle, P., Middle Cerebral Artery Occlusion in theYoung Rat. Stroke. 13:6, 1982). We have combined distal MCA occlusionwith ipsilateral common carotid ligation in an attempt to producereproducible, focal cerebral ischemic infarcts.

Adult male Fisher (F-344) rats 250,-300 g) were anesthetized in a boxcontaining halothane and then moved to a small animal anesthetic mask towhich 1.5% halothane in room air was provided for spontaneousinspiration (Levy, D. E., Zwies, A., Duffy, T. E., A Mask for Deliveryof Inhalation Gases to Small Laboratory Animals. Laboratory AnimalScience, Volume 30, 5:868-870, 1980). The skin on the ventral side ofthe neck and the left temporal-parietal region was shaved. An incisionwas made in the neck and the left common carotid artery was doublyligated and cut between the sutures. The incision was closed with 4-0silk. Another incision was then made behind the left eye and the skinwas held back with retractors. The exposed temporalis muscle waselectrocauterized (Jarit Bipolar Coagulator) and partially removed. Theupper part of the lower jaw bone was also removed. Deep surgery wasperformed with the aid of a Zeiss OPMI 99 surgical microscope. A 1 to2-mm diameter craniotomy was made about 1 mm anterior to where therostral end of the zygoma fuses to the squamosal bone. To prevent thedrill from going through the dura, the burr hole was not drilledcompletely through the skull. Bone remaining after drilling was removedwith forceps. The dura was pierced and reflected with a fine probe.

At this point the rat was injected with 0.3 ml of 2% Evans blue dye insaline via the tail vein. Evans blue binds to serum albumin and will notpass the blood-brain barrier unless damage has occurred, such as damageinduced by ischemia. A small hook was then positioned under the MCA andthe MCA was lifted away from the cortex. A jeweler-type bipolar forcepswas introduced and the MCA was electrocauterized and separated. Gelfoamwas put over the craniotomy and the wound was closed with 4-0 silk. Therats were then taken off the halothane and were allowed to wake up.Total anesthesia time was typically 30 minutes. Animals undergoing thisprocedure (MCAO rats) awoke from anesthesia within ten minutes ofbreathing room air alone again and were grossly indistinguishable fromunoperated rats.

On Day 2 following MCA occlusion, the rats were anesthetized withketamine (150 mg/kg, IP) and sacrificed. Cerebral tissue fixation wasinitiated by perfusion of 10% neutralized, buffered formalin for fiveminutes. Brains were removed and stored in the fixative until analysis.

For evaluation of the extent of cerebral ischemic injury, the brainswere cut coronally in three different locations. The first section wasat the level where the MCA was ligated. The other two sections were 2 mmanterior and 2 mm posterior to the first. Using an ausJena Citovalmicroscope with a drawing tube and an Apple II plus computer with aHouston Instrument digitizing pad, a software routine to measure thearea of the ischemic damage as indicated by the extent of Evans bluetissue extravasation was employed. The software package was purchasedfrom R&M Biometrics (Nashville, TN) and is titled Bioquant II. From thelesion areas (mm²) obtained from the Bioquant II program, we estimatedthe hemispheric extent (mm³) of ischemic damage between the anterior andposterior sections by computing and adding the volume of two truncatedcones.

In preliminary experiments the extent of cerebral ischemic injury wascompared in MCAO and sham-operated rats. Sham-operated rats underwent anidentical surgical procedure except that the bipolar electrocauteryforceps were activated away from the artery but within the subarachnoidspace.

The area of ischemic damage was significantly larger in the MCAO ascompared to the sham-operated rats in the anterior and middle coronalsections, represented both as area of injury and area of injury as apercentage of the entire coronal section. The posterior coronal sectionshowed a tendency toward a larger area of injury in MCAO animalsrelative to sham-operated controls.

Combined middle cerebral and ipsilateral common carotid artery ligationcaused ischemic cerebral tissue injury which was consistently greater inextent than that injury which occurs as a result of sham operationalone. The area of injury was greatest in the anterior and middlecoronal sections, which is consistent with the area of middle cerebralarterial distribution in the rat.

The Bioquant II image analysis system was used to quantitate ischemicinjury as it was identified by Evans blue extravasation. The variabilityin extent of ischemic cerebral tissue injury in this model is smallenough that it can be reasonably anticipated that successful treatmentcan be detected by reduction in the lesion size.

Compounds were administered in solution (the vehicle was saline, pHadjusted to be 3-5, and was without effects in the MCAO assay) byintraperitoneal injection (1.0 ml/kg body weight) 30 minutes and again24 hours after arterial occlusions.

The duration of anesthesia is that time elapsed between administrationof the test substance and the test animal regaining consciousness.

Tables I-IV below show MCAO and anesthetic activity for the disclosedcompounds.

                                      TABLE I                                     __________________________________________________________________________    AMINOBENZOTHIAZOLES: .sup.1 MCAO ACTIVITY                                     6-Substituted-2-Aminobenzothiazoles                                            ##STR2##                                                                                           .sup.2 Anesthesia                                                                    .sup.3 Collateral Zone                                                                 .sup.4 Hemispheric                      Compound        Dose  (Yes or No)                                                                          Infarct  Infarct                                 Number                                                                              R (6-position)                                                                          (mg/kg)                                                                             (duration)                                                                           (% of Control)                                                                         (% of Control)                          __________________________________________________________________________    1     H         10    No     36       61                                                      30    Yes (2 hr)                                                                           11       47                                      2     SMe       10    --     72       88                                                      30    --     100      106                                     3     Me        10    Yes (2-3 hr)                                                                         54       77                                                      30    Yes (4-6 hr)                                                                         14       51                                      4     SO.sub.2 Me                                                                             10    No     77       83                                                      30    No     58       86                                      5     Cl         3    No     77       83                                                      10    No     58       86                                            Cl        10    No     23       63                                                      30    Yes (>3 hr)                                                                          31       66                                      6     OEt       10    No     94       115                                                     30    No     16       59                                      7     Br        10    No     69       88                                                      30    Yes (>5 hr)                                                                          59       68                                      8     NO.sub.2 (Example 3)                                                                    10    No     92       93                                                      30    Yes (4 hr)                                                                           24       62                                      9     OCF.sub.3  3    No     117      99                                                      10    No     43       66                                                      15    No     42       82                                                      30 (N = 2)                                                                          Yes (1-2 hr)                                                                         0        44                                      10    CF.sub.3   3    No     156      131                                                     10    No     51       53                                      11    F         10    No     42       76                                                      30    Yes (<4 hr)                                                                          96       96                                      __________________________________________________________________________

                                      TABLE II                                    __________________________________________________________________________    AMINOBENZOTHIAZOLES: .sup.1 MCAO ACTIVITY                                     4-Substituted-2-Aminobenzothiazoles                                            ##STR3##                                                                                       .sup.2 Anesthesia                                                                    .sup.3 Collateral Zone                                                                 .sup.4 Hemispheric                          Compound     Dose (Yes or No)                                                                          Infarct  Infarct                                     Number                                                                              R (4-position)                                                                       (mg/kg)                                                                            (duration)                                                                           (% of Control)                                                                         (% of Control)                              __________________________________________________________________________    12                                                                            4,6-dimethyl 10   No     91       79                                                       30   No     68       76                                          13    OMe     3   No     85       90                                                       10   Yes (>5 hr)                                                                          115      121                                         14    Me     10   No     69       72                                                       30   No     40       54                                          15    Cl     10   Yes (2 hr)                                                                           63       75                                                       30   Yes (>5 hr)                                                                          15       51                                          16    CF.sub.3                                                                             10   No     63       99                                                       30   Yes    15       61                                          17                                                                            4,6-difluoro                                                                        10     No   137    139                                                               30   Yes    105      115                                         __________________________________________________________________________

                  TABLE III                                                       ______________________________________                                        AMINOBENZOTHIAZOLES: .sup.1 MCAO ACTIVITY                                     5-Substituted-2-Aminobenzothiazoles                                                                     Anesthe-                                                                      sia           .sup.4 Hemi-                          Com                       (Yes or       spheric                               pound                     No)    Infarct                                                                              Infarct                               Num-  R (5-posi- Dose     (dura- (% of  (% of                                 ber   tion)      (mg/kg)  tion   Control)                                                                             Control)                              ______________________________________                                        18    -OMe       10       No     124    117                                                    30       No     54     82                                    19    -CF.sub.3  10       No     48     63                                          (Example 7)                                                                              30       No     53     79                                    20    -4,5-(C.sub.4 H.sub.4)                                                                   30       Yes    81     92                                    ______________________________________                                    

                                      TABLE IV                                    __________________________________________________________________________    AMINOBENZOTHIAZOLES: .sup.1 MCAO ACTIVITY                                     2-Substituted-benzothiazoles                                                                           .sup.2 Anesthesia                                                                    .sup.3 Collateral Zone                                                                 .sup.4 Hemispheric                   Compound            Dose (Yes or No)                                                                          Infarct  Infarct                              Number                                                                              R             (mg/kg)                                                                            (duration)                                                                           (% of Control)                                                                         (% of Control)                       __________________________________________________________________________    21    NHEt (Example 5)                                                                            10   No     62       71                                                       30   No     116      89                                   22    NHCH.sub.2 Ph(Example 6)                                                                    10   No     56       76                                                       30   No     98       89                                   23                                                                                   ##STR4##     10 30                                                                              No No  66 18    84 72                                __________________________________________________________________________     .sup.1 MCAO Activity: Compounds were given IP in solution 30 minutes afte     stroke onset and again 24 hours later.                                        .sup.2 Anesthesia:                                                            Yes  Rats showed impaired consciousness and lack of righting reflex after     dosing.                                                                       No  Rats may have been ataxic but could right themselves and responded to     noxious stimuli after dosing.                                                 .sup.3 Collateral Zone Infarct: Posterior section of ipsilateral cerebral     hemisphere  infarct is measured in mm.sup.2 and presented as a percentage     of respective historical control sections.                                    .sup.4 Hemispheric Infarct: Estimated total hemispheric volume measured i     mm.sup.3 and presented as a percentage of historical controls.           

Collateral Zone (C) and Hemispheric (H) Infarct Volumes are expressed asPercent of Historical Control Rats (N=30) and were measuredquantitatively after combined middle cerebral and ipsilateral carotidartery occlusion (MCAO) according to the protocol described above. Thecollateral zone (posterior cerebral tissue section) was assessed as aspecific indicator of injury to an area of the brain away from thearterial occlusion site. The hemispheric volume was an assessmentcomputed from multiple cerebral tissue sections to provide an overallimpression of infarct size.

For the therapeutic uses described above, the usual mammalian dosagerange for a 70 kg human subject is from 1 to 2100 mg per day or 0.01 mgto 30 mg per kg of weight per day; optionally in divided portions.Determination of the proper dosage for a particular situation is withinthe skill of the art.

Pharmaceutical compositions of the compound of the present invention orits salts are produced by formulating the active compound in dosage unitform with a pharmaceutical carrier. Some examples of dosage unit formsare tablets, capsules, pills, powders, aqueous and nonaqueous oralsolutions, and suspensions and parenteral solutions packaged incontainers containing either one or some larger number of dosage unitsand capable of being subdivided into individual doses. Some examples ofsuitable pharmaceutical carriers, including pharmaceutical diluents, aregelatin capsules; sugars such as lactose and sucrose; starches such ascorn starch and potato starch; cellulose derivatives such as sodiumcarboxymethyl cellulose, ethyl cellulose, methyl cellulose, andcellulose acetate phthalate; gelatin; talc; stearic acid; magnesiumstearate; vegetable oils such as peanut oil, cottonseed oil, sesame oil,olive oil, corn oil, and oil of theobroma; propylene glycol; glycerine;sorbitol; polyethylene glycol; water; agar; alginic acid; isotonicsaline, and phosphate buffer solutions; as well as other compatiblesubstances normally used in pharmaceutical formulations. Thecompositions of the invention can also contain other components such ascoloring agents, flavoring agents, and/or preservatives. Thesematerials, if present, are usually used in relatively small amounts. Thecompositions can, if desired, also contain other therapeutic agents.

The percentage of the active ingredient in the foregoing compositionscan be varied within wide limits, but for practical purposes it ispreferably present in a concentration of at least 10% in a solidcomposition and at least 2% in a primarily liquid composition. The mostsatisfactory compositions are those in which a much higher proportion ofthe active ingredient is present.

Routes of administration of the subject compound or its salts are oral,parenteral, transdermal, or intranasal. For example, a usefulintravenous dose is between 0.01 and 10.0 mg/kg. A preferred intravenousdose is 0.1 to 5.0 mg/kg. A still further preferred dose is 0.1 to 1.0mg/kg. A useful oral dose is 0.01 to 30 mg/kg. A preferred oral dose is0.1 to 10 mg/kg. A further preferred dose is 1.0 to 5.0 mg/kg. All ofthe above are as would occur to a person skilled in the art.

The following examples are provided to enable one skilled in the art topractice the invention. These examples are not intended to limit thescope of the invention in any way but rather to be illustrative thereof.Many of the compounds of the invention are known and in some casescommercially available.

EXAMPLE 1 ##STR5##

To a stirred mixture of 4-isopropylaniline (10.0 g, 0.074 mol) andpotassium thiocyanate (14.38 g, 0.148 mol) in 100 mL of glacial aceticacid was added dropwise, bromine (11.83 g, 0.074 mol) in 25 mL glacialacetic acid, over 0.5 hours. The reaction mixture was stirred vigorouslyfor 24 hours at room temperature. The reaction mixture was poured overice, and the solution made basic to pH 10 with concentrated ammoniumhydroxide to produce a yellow precipitate. The2-amino-6-isopropylbenzothiazole was collected by filtration andrecrystallized from toluene (50% yield, m.p. 123°-124° C.).

    ______________________________________                                        calc. C      64.46   H    6.29  N    14.57 S    16.68                         found C      62.44   H    6.32  N    14.60 S    16.65                         ______________________________________                                    

EXAMPLE 2 ##STR6##

To a Stirred mixture of 9.3 g (0.074 mol) of 3-fluoro-4-methylanilineand 14.4 g (0.148 mol) potassium thiocyanate in 50 mL glacial aceticacid was added dropwise 11.8 g (0.074 mol) of bromine. The solution wasstirred at room temperature for 18 hours. The reaction solution waspoured over ice and basified to pH 10 with concentrated ammoniumhydroxide to yield a precipitate. The solid,2-amino-5-fluoro-6-methylbenzothiazole was collected by filtration andrecrystallized from ethanol or toluene.

EXAMPLE 3 ##STR7##

To a stirred mixture of 1-(4-nitrophenyl)-2-thiourea (15.0 g, 0.076 mol)in 20 mL of concentrated sulfuric acid was added dropwise, bromine (0.61g, 0.004 mol) in 10 mL concentrated sulfuric acid over 0.5 hours. Thereaction mixture was heated to 90° C., and stirred vigorously for 24hours. The reaction was cooled slowly to room temperature and quenchedby pouring over ice. The solution was made basic to pH 10 withconcentrated ammonium hydroxide, producing a yellow solid. The2-amino-6-nitro-benzothiazole was filtered and recrystallized fromethanol (85% yield, m.p. 246°-247° C.).

    ______________________________________                                        calc. C      43.07   H    2.58  N    21.53 S    16.43                         found C      42.71   H    2.46  N    21.58 S    16.79                         ______________________________________                                    

EXAMPLE 4 ##STR8##

To a solution of 2-amino-6-nitrobenzothiazole (10 g, 0.051 mol) in 100mL of tetrahydrofuran was added 3.0 g Raney-nickel active catalyst. Thereaction mixture was hydrogenated until hydrogen consumption ceased. Thereaction mixture was filtered through a Celite pad and the solution wasconcentrated under reduced pressure to produce a brown solid. The solidwas recrystallized from toluene, yielding 2,6-diaminobenzothiazole (50%yield, m.p. 202°-203° C.).

    ______________________________________                                        calc. C      50.88   H    4.27  N    25.43 S    19.41                         found C      50.71   H    4.42  N    25.43 S    19.80                         ______________________________________                                    

EXAMPLE 5 ##STR9##

To a stirred mixture of 2-chlorobenzothiazole (13.3 g, 0.077 mol),sodium carbonate (9.77 g, 0.092 mol) and sodium iodide (0.22 g, 0.0015mol) in 15 mL N,N-dimethylacetamide, was added phenethylamine (10.24 g,0.084 mol) in one portion. The reaction mixture was heated to 140° C.,stirred vigorously for four hours and allowed to cool slowly to roomtemperature. At this time the reaction was quenched with water producinga brown solid. The N-(2-phenethyl)-2-benzothiazolamine was collected byfiltration and recrystallized from di-isopropyl ether (8% yield, m.p.143° C.).

    ______________________________________                                        calc. C      70.80   H    5.55  N    11.02 S    12.61                         found C      70.80   H    5.76  N    11.05 S    12.82                         ______________________________________                                    

EXAMPLE 6 ##STR10## (As illustrative of literature procedures, a furthergeneral method for the preparation of the disclosed compounds givenhere)

To a stirred solution of 74.6 g (0.5 mol) of benzylisothiocyanate in 500mL toluene was added dropwise 46.6 g (0.5 mol) of aniline. The solutionwas refluxed 18 hours. After cooling, the reaction mixture wasconcentrated under reduced pressure. The residue was recrystallized froman appropriate solvent to yield N-phenyl-N'-benzylthiourea.Isothiocyanates which are not commercially available may be preparedfrom aliphatic or aryl primary amines by the following methods: Kuritaand Iwakura, Org. Synth. 59, 195; Jochims, Chem. Ber. 101, 1746 (1968);or Castro, Pena, Santos, and Vega, J. Org. Chem. 49, 863 (1984).

To a stirred solution of 12.1 g (0.05 mol) of N-phenyl-N'-benzylhioureain 150 ml of glacial acetic acid was added dropwise 8.0 g (0.05 mol) ofbromine in 60 mL of glacial acetic acid. The reaction was poured into 10volumes of water and made basic with concentrated ammonium hydroxide. Asolid precipitated from the aqueous solution and was filtered. The solidcould be recrystallized from an appropriate solvent to yieldN-benzyl-2-benzothiazolamine.

EXAMPLE 7 ##STR11## 3-Nitro-4-thiocyanatebenzotrifluoride

To a stirred solution of 20.6 g (0.10 mol)4-amino-3-nitrobenzotrifluoride in 30 mL conc. H₂ SO₄ and 30 mL H₂ O at0° C. was added dropwise 37.5 mL 20% sodium nitrite. The mixture wasstirred for 90 minutes at 0°-5° C. Potassium thiocyanate (10 g in 20 mLH₂ O) was added dropwise and stirred 15 minutes. The reaction was pouredinto a vigorously stirred slurry of 18 g (0.148 mol) copperthiocyanatein 60 mL H₂ O. Gas evolution began and the mixture foamed. The reactionwas stirred two hours at 3° C. and then heated to 70° C. for 20 minutes.The reaction was cooled to 25° C. and stirred an additional 18 hours.The solution was filtered and the water was extracted with toluene(3×100 mL). The toluene layer was dried (Na₂ SO₄), filtered, andconcentrated under reduced pressure to yield a purple oil. The productwas purified by silica gel chromatography. The column was elutedinitially with hexane followed by hexane/CH₂ Cl₂ (7:3) to yield an oilwhich was crystallized from heptane to yield a yellow solid, m.p.72°-73° C.

    ______________________________________                                        calc.    C     38.71     H   1.22    N   11.29                                found    C     38.62     H   1.17    N   11.10.                               ______________________________________                                    

2-amino-5-trifluoromethylbenzothiazole hydrochloride

To a vigorously stirred solution of 4.0 g (0.16 mol)3-nitro-4-thiocyanatebenzotrifluoride in 50 mL conc. HCl was added 16.0g (0.135 mol) granulated tin over one hour. The reaction changed from anorange to very pale yellow to white. The reaction was stirred at 25° C.for 20 h. The reaction solution was diluted with H₂ O (250 mL) and conc.NH₄ OH was added dropwise. The product precipitated along with the tinsalts. The solid was filtered and boiled in CHCl₃ (3×200 mL). Theaqueous layer was extracted with CHCl₃. All the CHCl₃ washings werecombined, dried (MgSO₄), filtered, and concentrated under reducedpressure to yield a dark brown solid. The crude benzothiazole wasdissolved in hot Et₂ O and filtered. To the filtrate was added asolution of freshly prepared Et₂ O/HCl. The product precipitate wasfiltered and washed with Et₂ O to yield a white solid m.p. 255°-257° C.

    ______________________________________                                        calc.    C     37.73     H   1.98    N   11.00                                found    C     37.50     H   2.33    N   10.76                                ______________________________________                                    

We claim:
 1. A method for treating cerebrovascular disorders whichcomprises administering to a patient in need thereof a therapeuticallyeffective amount of a compound of the formula ##STR12## or apharmaceutically acceptable salt thereof in unit dosage form wherein R¹and R² are hydrogenR₃ is hydrogen; R₄ is lower alkyl substituted by asubstituted or unsubstituted pyrrolidine, piperidine, pyridine orthiophene wherein the substituents are a straight or branched alkyl oralkenyl of from one to six carbon atoms.
 2. A method for treatingcerebrovascular disorders which comprises administering to a patient inneed thereof a therapeutically effective amount of2-[[2-(1-methyl-2-pyrrolidinyl)ethyl]amino]-benzothiazole.